1. Field of the Invention
The invention relates to axial hydroxy and axial carboxylate platinum (IV) compounds which possess antitumor activity. Certain of the compounds of the present invention also possess excellent water-solubility which makes them more efficacious in pharmaceutical dosage form than known chemically effective platinum derivatives; other compounds are liposoluble which indicates their potential use in liposomes, for incorporating into the internal oil phase of an oil/water emulsion for oral or parenteral dosage forms, for injection as oil solutions directly into solid tumors, or for topical use in ointments, gels, and the like. The compounds according to the present invention demonstrate properties superior to other platinum compounds known in the art, such as lower kidney or bone marrow toxicity, as well as high tumor activity.
2. Description of the Prior Art
A large number of platinum II and platinum IV complexes have been evaluated for use as antitumor agents.
Many such derivatives have exhibited in vitro and in vivo activity against neoplastic cells. A platinum (II) compound (cis-dichlorodiammine platinum (II)) is commercially available for treatment of certain human tumors. However, most of these derivatives have undesired side effects when administered in vivo or are not very . soluble in aqueous fluids.
Published patents, patent applications, and technical journal documents relating to platinum (IV) derivatives are as follows:
U.S. Pat. No. 4,466,924 relates to platinum compounds of the type ##STR3## wherein X is halogenoid, a sulphate radical, a substituted carboxylate radical, or an unsubstituted carboxylate radical and Y is halogenoid, a hydroxyl group, a nitrate group, or acarboxylate. However, only tetra-halogen derivatives and dihalo-dihydroxy derivatives are shown as particular species compounds.
U.S. Pat. No. 4,250,189 relates to platinum compounds of the type ##STR4## wherein Z is absent or is halogen, pseudohalogen (e.g., cyanide, cyanate, thiocyanate, and azide), or hydroxy. sulphate, phosphate, nitrate, carboxylate, substituted carboxylate, water, halogen, or pseudohalogen. No axial carboxylate derivatives are disclosed or claimed.
U.S. Pat. Nos. 4,581,224 and 4,594,238 relate to the process for using dithiocarbamic compounds to reduce harmful side effects caused by the administering of platinum complex compounds. Among other platinum compounds generally outlined at Page 11 in each of the above referenced patents were those compounds relating to the general formula ##STR5## wherein a number of substituents for X.sup.1, X.sup.2, X.sup.3, and X.sup.4 are generally described, but halogen substituents were preferred for X.sup.1 and X.sup.2 and --OH or water molecules were preferred for X.sup.3 and X.sup.4. The platinum compounds are very generally and broadly set forth, and no examples of compounds or subgeneri are disclosed wherein the equatorial substituents are halogen when at least one of the axial substituents is a carboxylate derivative.
U.S. Pat. No. 4,119,654 relates to platinum compounds of the type ##STR6## wherein X and Y are halogenoid and A and B each independently represent branched chain aliphatic amine groups having the formula EQU C.sub.n --R.sub.2n+1 --NH.sub.2
wherein n is an integer from 3-9 and wherein all of the R groups are the same or different and are selected from the group consisting of hydrogen, alkyl, aryl, alkanyl, aralkyl, halogen, pseudohalogen, hydroxy, carbonyl, formyl, nitro, amido, amino, sulfonic acid, sulfonic acid salt, carboxylic acid, and carboxylic acid salt.
U.S. Pat. No. 4,119,653 relates to platinum compounds of the type ##STR7## wherein X and Y are halogenoid and A and B each independently represent ammine (NH.sub.3) or straight chain aliphatic amine groups having the formula EQU C.sub.n --R.sub.2n+1 --NH.sub.2
in which n is an integer from 3-9 and R is as defined in U.S. Pat. No. 4,119,654, referenced above.
U.K. Patent Application 2,006,213A relates to platinum compounds of the type ##STR8## wherein inter alia, Z is hydroxy, X and Y are halogenoid, and A and B are alicyclic amine groups or C-substituted alicyclic amine groups of the formula EQU cyclo-C.sub.n --R.sub.2n+1 --NH.sub.2
in which n=3-7 and R is as defined in U.S. Pat. No. 4,119,654, referenced above.
U.K. Patent Application 2,148,891A relates to compounds of the type ##STR9## wherein R.sub.1 and R.sub.2 represent C.sub.1 -C.sub.3 alkyl or jointly represent C.sub.3 -C.sub.6 alkylene, X represents halogen, ##STR10## in which R.sub.3 is lower alkyl or --OM, wherein M is monovalent cation; Y is OH or halogen; and n=0 or 1.
U.S. Pat. No. 4,658,047 relates to 1,2-diaminocyclohexane tetrachloro platinum (IV) isomers of the type ##STR11## wherein the compounds are cis-, trans (d,l), trans-1, or trans-d.
U.S. Pat. No. 4,431,666 relates to compounds of the type ##STR12## wherein R.sub.1 and R.sub.2 are each independently hydrogen or an alkyl, aryl, or aralkyl group having 1-20 carbon atoms or a cycloalkyl group having 3-7 carbon atoms, while R.sub.1 and R.sub.2 together may be a cycloalkyl group having 3-7 carbon atoms, R.sub.3 and R.sub.4 are each independently hydrogen or alkyl, aryl or aralkyl groups having 1-20 carbon atoms, and X and Y are each independently an anionic group.
Some acylated platinum (IV) derivatives are described in the literature. For example, Zh. Neorg. Khim 27 (5): 1234-1238, 1982, relates to a platinum complex of the formula ##STR13## Int. J. Mass. Spectrom. Ion. Phys., 48, 177-180, 1983, relates to platinum complexes of the formulae ##STR14## Chemical Abstracts 101 (20): 182625s relates to platinum complexes of the formula ##STR15##